Obesity is at epidemic proportions with more than 300 million obese people worldwide and constantly rising. Obesity is not only a cosmetic problem, but a life-threatening disease, reducing quality of life as well as its longevity. Obesity increases the risk for many dreadful diseases, including type 2 diabetes, cardiovascular diseases and cancer, and is associated with insulin resistance, glucose intolerance and dyslipidemia. Therefore, there is an important need to understand the mechanisms related to obesity and find ways to combat the deadly disease and its complications.
As a treatment perspective, finding an appropriate cure for obesity and related complications is extremely challenging due to the physiological and biochemical complexity of the disease. However, it is clear that changing energy homeostasis in favor of energy expenditure vs. energy intake will help in combating obesity. Therefore, identification of cellular mechanisms able to increase whole body energy expenditure (“negative energy balance”) are advantageous as targets for obesity therapy.
One option to increase energy expenditure is the uncoupling of mitochondrial respiration in brown adipose tissue (BAT). In this process, there is a regulated proton leak in the inner mitochondrial membrane through uncoupling protein 1 (UCP1), resulting in the dissipation of energy as heat and increased fuel oxidation. This suggests that high amounts of active BAT would be beneficial in the battle against obesity. Unfortunately, however, human adults are not considered to have sufficient amounts of BAT, in contrast to small mammals and newborn humans. Therefore, finding ways to increase the activity of BAT in adulthood would be beneficial in combating obesity by increasing the oxidation of nutrients in the body.
The recent discovery of BAT in human adults and a better understanding of BAT development have encouraged the quest for new alternatives to treat obesity since obese individuals seem to have less brown adipose tissue mass/activity than do their lean counterparts. It is noteworthy that the activity of BAT is approximately fourfold higher in the lean group than in the overweight/obese group.
From an anatomical point of view, brown fat cells are localized in two types of depots: discrete and diffuse. In humans, BAT of discrete location is found in cervical-supraclavicular, perirenal/adrenal, and paravertebral regions around the major vessels and is probably present to generate and distribute heat to maintain core temperature. In distinction, diffuse brown fat cells exist in white adipose and appear in response to cold exposure or chronic catecholamine stimulation.
The metabolic syndrome, which comprises a cluster of metabolic abnormalities such as hyperlipidaemia, diabetes mellitus and hypertension, is a widespread and increasingly prevalent disease in western and industrialized countries.
Non-alcoholic fatty liver disease (NAFLD) is now recognized as the hepatic manifestation of the metabolic syndrome and is emerging as one of the most common causes of chronic liver disease worldwide. NAFLD encompasses a wide disease spectrum ranging from simple hepatic steatosis to steatohepatitis, advanced fibrosis and cirrhosis. Liver-related morbidity and mortality due to NAFLD are observed in patients who have advanced fibrosis and cirrhosis. The mechanisms that accelerate the progression of simple steatosis towards more debilitating and advanced stages of NAFLD remain poorly understood, but generally assume that it implies a two hit theory. Hepatic fat accumulation represents the ‘first hit’ of the disease and it has been suggested that fat accumulation in hepatocytes is the hallmark of NAFLD and leaves them highly vulnerable to a ‘second hit’, for example, injury by oxidative stress and inflammatory cytokines, such as TNF-α, monocyte chemoattractant protein-1 (MCP-1) and other cytokines.
At present, no pharmacotherapy is available that can fully reverse or prevent steatohepatitis. Therefore, it is necessary to develop effective therapies for the treatment of NAFLD and the discovery of molecules or compositions that may reduce the risk of NAFLD would be useful.
Colorectal cancer (CRC) is the second leading cause of death from cancer among adults in the United States as well as in Israel. Mortality rates are in constant rise, which is why there is so much importance in finding factors that would reduce morbidity. As a treatment perspective, finding an appropriate cure for cancer and related complications is extremely challenging due to the complexity of the mechanisms involved in this disease progression. Therefore, identification of cellular mechanisms involved and molecules able to suppress colon cancer cell proliferation and progression could be advantageous for cancer treatment.
Caveolin-1 (Cav-1) is the major protein component of caveolae, specialized lipid rafts that are recognized in electron micrographs as 50-100 nm invaginations of the plasma membrane. Caveolae are found primarily in terminally differentiated mesenchymal cells including adipocytes, endothelial cells and fibroblasts suggesting a possible role of Cav-1 as a negative regulator of cell proliferation. Interestingly, Cav-1 has been implicated in the pathogenesis of oncogenic cell transformation, tumorigenesis and metastasis. Cells, including tumor cells, constantly face the decision of whether to survive and proliferate or to undergo programmed cell death (apoptosis). Therefore, identifying the pathways that are pro-apoptotic or anti-apoptotic has important implications for controlling tumor cell growth.